The first step in the cytotoxic action of diphtheria toxin (DT) is binding of the toxin molecule to the surface of a susceptible cell. The cellular receptor for toxin binding is the membrane-anchored precursor of heparin-binding EGF-like growth factor (HBEGF). We have determined the crystal structure of DT in complex with HBEGF at 2.65 E resolution. HBEGF is homologous to heregulin, another growth factor from the EGF family. Heregulin is the activating ligand for the HER4 receptor, which is overexpressed in breast carcinoma cells. The detailed structural information on the atomic interactions between DT and HBEGF is serving as a basis for designing mutations that will alter the binding specificity of DT. The long-term objective is an engineered DT that will recognize heregulin and serve as a therapeutic agent for inhibiting growth of breast cancer cells.